title: Improvement of brain energy metabolism and cholinergic functions contributes to the beneficial effects of silibinin against streptozotocin induced memory impairment.
abstract: Recently, silibinin, a clinically used hepatoprotectant, has been reported to prevent amyloid beta induced memory impairment by reducing oxidative stress and inflammation in mice brain. However, the exact mechanism of neuroprotective effect of silibinin has not been properly studied especially in context of brain energy metabolism and cholinergic functions, the essential factors that undergo impairment in Alzheimer's disease. Therefore, the present study investigated the effect of silibinin on impairment in memory, brain energy metabolism and cholinergic function following intracerebral (IC) streptozotocin (STZ) administration in mice. STZ (0.5mg/kg), administered twice at an interval of 48h, caused significant memory impairment tested by Morris water maze. Further, STZ significantly decreased ATP and increased synaptosomal calcium level in mice brain. Increased oxidative and nitrosative stress was also observed in IC STZ injected mice brain. STZ IC induced memory impairment is associated with increased activity and mRNA expression of acetylcholinesterase (AChE) and decreased α-7 nicotinic acetylcholine receptor (α-7-nAChR) mRNA expression in mice brain. Pretreatment with silibinin (100 and 200mg/kg, po) attenuated STZ induced memory impairment by reducing oxidative and nitrosative stress and synaptosomal calcium ion level. Further, silibinin dose dependently restored ATP level indicating improvement in brain energy metabolism. The activity and mRNA expression of AChE was restored by silibinin. Moreover, α-7-nAChR mRNA expression was significantly increased by silibinin in STZ treated mice brain. The present study clearly demonstrates that beneficial effects of silibinin in STZ induced memory impairment in mice is due to improvement in brain energy metabolism and cholinergic function.
authors.affiliation: Division of Pharmacology, Central Drug Research Institute, CSIR, Lucknow, UP, India.
authors.forename: Santoshkumar
authors.initials: S
authors.lastname: Tota
authors.forename: Pradeep Kumar
authors.initials: PK
authors.lastname: Kamat
authors.forename: Rakesh
authors.initials: R
authors.lastname: Shukla
authors.forename: Chandishwar
authors.initials: C
authors.lastname: Nath
mesh_terms: D000110:Acetylcholinesterase / Q000096:biosynthesis*; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology / Q000627:therapeutic use*; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D004734:Energy Metabolism / Q000187:drug effects*; D005978:Glutathione / Q000378:metabolism; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D018782:Maze Learning / Q000187:drug effects; D008569:Memory Disorders / Q000139:chemically induced / Q000188:drug therapy*; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects; D026361:Reactive Nitrogen Species / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D011978:Receptors, Nicotinic / Q000096:biosynthesis*; D000077385:Silybin; D012838:Silymarin / Q000494:pharmacology / Q000627:therapeutic use*; D013311:Streptozocin; D013574:Synaptosomes / Q000378:metabolism; D064569:alpha7 Nicotinic Acetylcholine Receptor
chemical_list: D000975:Antioxidants; C579166:Chrna7 protein, mouse; D026361:Reactive Nitrogen Species; D017382:Reactive Oxygen Species; D011978:Receptors, Nicotinic; D012838:Silymarin; D064569:alpha7 Nicotinic Acetylcholine Receptor; D000077385:Silybin; D008315:Malondialdehyde; D013311:Streptozocin; D000255:Adenosine Triphosphate; D000110:Acetylcholinesterase; D005978:Glutathione; D002118:Calcium